GSK 2336805 / J&J, GSK - LARVOL DELTA

Influenza virus infection reprograms cholesterol biosynthesis to facilitate virus replication by the TAK1-RORγ axis. (PubMed, PLoS Pathog) - "RORγ knockout and treatment with two RORγ inhibitors, XY018 and GSK805, suppress IAV-induced HMGCR expression, cholesterol biosynthesis, and viral replication...Furthermore, XY018 treatment reduces both viral replication and inflammation in the lungs of IAV-infected mice. Our findings provide novel mechanistic insights into how IAV infection upregulates cholesterol biosynthesis to facilitate viral replication."

Journal • Infectious Disease • Inflammation • Influenza • Respiratory Diseases • MAPK8 • TGFB1

Inhibition of RORγt suppresses both retinal and choroidal neovascularization in mice. (PubMed, Exp Eye Res) - "Additionally, GSK805 treatment downregulated pro-inflammatory cytokines (IL-22 and IL-17A), angiogenic factors (angiopoietin 2, PDGF-B, and PDGFR-β), and inflammasome components (NLRP3 and ASC), while modulating macrophage polarization by reducing M1 markers and increasing M2 markers. These findings reveal that RORγt plays a supportive role in NV by influencing key inflammatory and angiogenic pathways, suggesting that RORγt inhibition may represent a promising therapeutic strategy for NV-related retinal diseases."

IO biomarker • Journal • Preclinical • Age-related Macular Degeneration • Ophthalmology • Retinal Disorders • IL17A • IL22 • IL23A • NLRP3 • PDGFRB

Novel RORγt inverse agonists limit IL-17-mediated liver inflammation and fibrosis. (PubMed, J Immunol) - "As of week 3, mice were treated with the 2 novel inverse agonists (TF-S10 and TF-S14) and GSK805 as a positive control...This was accompanied by diminished collagen deposition as measured by Picrosirius Red staining (P < 0.001). In conclusion, our results suggest that inhibition of the IL-17A pathway could be a promising therapeutic strategy for liver fibrosis."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • CD4 • CD8 • COL1A1 • IL17A • ITGAM • TGFB1

GSK805 inhibits alpha-smooth muscle expression and modulates liver inflammation without impairing the well-being of mice. (PubMed, FASEB J) - "Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well-being."

Journal • Preclinical • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • Primary Biliary Cholangitis • IFNG • TNFA

TBD (IMMUNOLOGY 2024) - "As of week 3, mice were treated with two novel pharmacological inhibitors of IL17A or GSK805 as a positive control (10 mg/Kg/day)...Finally, the inhibitors reduced the expression of the profibrogenic genes (Col1a1, Acta, Loxl2 and Tgfβ) (p<0.001) and reduced collagen deposition as measured by Picro sirius red area (p<0.05). In conclusion, our data suggest that inhibition of the IL17 pathway is a viable therapeutic strategy for liver fibrosis."

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • CD4 • CD8 • COL1A1 • IL17A • ITGAM • TGFB1

Discovery of Biaryl Amide Derivatives as Potent, Selective, and Orally Bioavailable RORγt Agonists for Cancer Immunotherapy. (PubMed, J Med Chem) - "Starting from the reported RORγt inverse agonist GSK805 (1), "functionality switching" and structure-based drug optimization led to the discovery of a promising RORγt agonist lead compound 14, which displayed potent and selective RORγt agonist activity and significantly improved metabolic stability. With excellent in vivo pharmacokinetic profiles, compound 14 demonstrated robust efficacy in preclinical tumor models of mouse B16F10 melanoma and LLC lung adenocarcinoma. Taken together, current studies indicate that 14 deserves further investigation as a potential lead RORγt agonist for cancer immunotherapy."

Journal • Lung Adenocarcinoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL17A

Characterization of ccl20a.3 and ccl20l as gene markers for Th17 cell in turbot. (PubMed, Fish Shellfish Immunol) - "Furthermore, through a Th17 lineage-specific transcription factor RORc inhibitor GSK805 treatment, we found that the expression of ccl20a.3 and ccl20l was significantly impaired, compared with other T cell markers. Besides, we also found that ccl20a.3 and ccl20l exhibited the same dynamic response with the classical markers that were identified in Th17 cells during bacterial infection. Taken together, these results provide potential gene markers for better understanding of the dynamic immune responses of Th17 cells in teleost fish."

Journal • Infectious Disease • Ophthalmology • CCL20 • IL17A • IL22

α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease. (PubMed, Brain Behav Immun) - "Together, our data suggest that α-Syn promotes the transcription of RORC in circulating CD4 T cells, including Tregs and Th17 cells, to impair the stability of Tregs and promote the differentiation of Th17 cells in PD. Inhibition of RORγt attenuated the apoptosis of DA and alleviated the increase in Th17 cells and decrease in Tregs in PD."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • CD4 • FOXP3 • IL17A

Nuclear receptor RORγ inverse agonists/antagonists display tissue- and gene-context selectivity through distinct activities in altering chromatin accessibility and master regulator SREBP2 occupancy. (PubMed, Pharmacol Res) - "We report here that inverse agonists/antagonists of RORγ such as VTP-43742 derivative VTP-23 and TAK828F, which can potently inhibit the inflammatory gene program in Th17 cells, unexpectedly lack high potency in inhibiting the growth of TNBC tumor cells. In contrast, antagonists such as XY018 and GSK805 that strongly suppress tumor cell growth and survival display only modest activities in reducing Th17-related cytokine expression...Together, our study shows for the first-time that structurally distinct RORγ antagonists possess different or even contrasting activities in tissue/cell-specific manner. Our findings also highlight that the activities at natural chromatin are key determinants of RORγ modulators' tissue selectivity."

Journal • Breast Cancer • Immunology • Oncology • Solid Tumor • Triple Negative Breast Cancer • IL17A

Therapeutic targeting RORγ with natural product N-hydroxyapiosporamide for small cell lung cancer by reprogramming neuroendocrine fate. (PubMed, Pharmacol Res) - "Therapeutically, N-hydap exhibited a strong inhibitory effect on tumor growth and did not show significant toxicity in SCLC mice xenograft models. Taken together, RORγ could be an attractive target for SCLC and thus N-hydap can be a promising therapeutic drug candidate for SCLC by inhibiting the RORγ activation."

Journal • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • AURKA • DLL3 • TUBB3

Ontogeny of RORγt cells in the intestine of newborns and its role in the development of experimental necrotizing enterocolitis. (PubMed, Cell Biosci) - "Our data reveal the high proportion of RORγt cells in newborn mice may directly contribute to the development of NEC."

Journal • Gastrointestinal Disorder • IL17A

An all-oral phase IIa study combining simeprevir, TMC647055 and JNJ56914845 in hepatitis C patients to be initiated (Medivir Press Release) - P2a, N=40; "Medivir...announces the initiation of a phase IIa trial in chronic genotype 1 hepatitis C infected patients to evaluate the efficacy, safety and tolerability of a 12-week combination therapy of simeprevir, TMC647055 and JNJ56914845....The trial will evaluate genotype 1a and 1b HCV-infected patients who are either treatment-naïve or who have relapsed after prior treatment with interferon and ribavirin."

New P2a trial • Hepatitis C Virus

Achillion: Oppenheimer Healthcare Conference (Achillion) - Anticipated launch of simeprevir + GSK 2336805 + TMC647055/ribavirin triple combo for hep C infection in 2016/2017

Anticipated launch • Hepatitis C Virus

New data on simeprevir presented at the conference of the Asian Pacific Association for the study of the liver (Medivir Press Release) - P2, N=104; NCT01724086; Sponsor: Janssen; "...up to 95% cure rates were achieved in HCV genotype (GT)1 infected patients treated with...simeprevir, TMC647055/ritonavir and JNJ-56914845." P3, N=457; NCT01725529; Sponsor: Janssen; "...89-91% were cured with simeprevir in combination with pegylated interferon (P) and ribavirin (R) for 12 weeks followed by PR [pegylated interferon-ribavirin] for a further 12 or 36 weeks." P3, N=213; NCT01846832; Sponsor: Janssen; "In the GT1 study arm 76% of the patients were eligible to shorten treatment and of those 66% achieved SVR12 (were cured). In the GT4 study arm 48% of the patients were eligible for shortened treatment and of those with evaluable outcome at the time of analysis 94% had achieved SVR4."

Anticipated conference • P2 data • P3 data • Hepatitis C Virus